1. Field of the Invention
The invention relates to oral dosage forms of benzonatate useful for a tussive and anti-tussive/combination applications.
2. Description of the Related Art
Benzonatate is a non-narcotic oral antitussive (cough suppressant) drug that works by anesthetizing the tissues of the lungs and pleura responsible for the cough reflex. Benzonatate is chemically related to anesthetic agents of the para-aminobenzoic acid class (e.g., procaine; tetracaine). Benzonatate anesthetizes the stretch receptors in the respiratory passages, reducing the cough reflex. As a non-narcotic with little or no abuse potential, benzonatate is a useful drug for treating cough. Further, benzonatate does not have many of the serious side effects that narcotic cough compounds such as codeine and hydrocodone have which include:
Narcotic Side Effects                Overdose, respiratory depression        Drug interactions                    Alcohol, minor tranquilizers, other CNS drugs                        Constipation, sedation        Abuse/dependence        Psycho/motor effects        
Due to these side effects, many patients cannot take narcotic cough products:                Pain patients, abuse history, elderly, young children, COPD patients, critically ill, military/police/fire/health transportation workers, pregnant & post-partum women        
In spite of the many reasons to use non-narcotic cough preparations, current formulations of benzonatate have a serious safety issue that can offset its benefits as a non-narcotic alternative to codeine and hydrocodone. Current formulations of benzonatate, if released in the mouth through dissolution, either by contact with saliva or aided by chewing or sucking, can rapidly cause oropharyngeal anesthesia that may lead to adverse events including choking.
Benzonatate has a secondary pharmacologic effect as a local anesthetic. If the drug is released in the oral cavity serious adverse effects can occur. In the TESSALON™ prescription drug label, the Signs and Symptoms section states:                “If capsules are chewed or dissolved in the mouth, oropharyngeal anesthesia will develop rapidly. CNS stimulation may cause restlessness and tremors which may proceed to clonic convulsions followed by profound CNS depression”.        
The formulations of the invention preserve the advantages of benzonatate while eliminating or diminishing hazards of its use. The inventive formulations of benzonatate use ion exchange resin technology to diminish or eliminate the choking hazard and adverse events if the product is released in the oral mucosa. It is believed that the use of ion exchange resins to create benzonatate compositions that can reduce or eliminate the choking and adverse effects associated with current formulations of benzonatate has not been previously disclosed. A review of the ion exchange literature and patents revealed the following pharmaceutical uses of ion-exchange resins:                Reduce Food Effects on Pharmacokinetic Release Rates        Taste Masking        Disintegrant/Superdisintegrant        Improved Dissolution        Powder Processing Aid        Drug Stabilization        Oral modified release formulations: Sustained Release, Controlled Release        
No patent or reference source reviewed mentioned the use of ion-exchange for preventing release of a drug in the oral cavity. No patent or reference explicitly or inherently disclosed ion-exchange resinates of benzonatate. Further, no source revealed the use of denatonium benzoate or similar noxious tasting agent to prevent patients from chewing or sucking a benzonatate capsule or tablet.
It had previously been found by the inventors that benzonatate can be resinated with both a strong acid resin and a weak acid resin at significant loadings, and that, surprisingly and unexpectedly, such resinates show substantially reduced buccal dissolution rates compared to neat benzonatate. More surprisingly and yet more unexpectedly, it has now been found that only a particular class of ion exchange resins can accurately load and unload all of the molecular species found in pharmaceutical grade benzonatate.
The Merck Index, 14th Ed., 2006 lists benzonatate (Merck No. 1096, CAS No. [104-31-4]) as a single compound having the formula C4H9—NH—C6H4—COO—(C2H4O)9—CH3. However, pharmaceutical grade benzonatate, for example, TESSALON™, is a mixture of butyl 4-aminobenzoate compounds having the general formula C4H9—NH—C6H4—COO—(C2H4O)n—CH3, and the structure shown below and in FIG. 1.

The quantity n is the number of ethoxy units in a compound of this mixture. The quantity n is typically in the range of from 3 to about 17.